Dementia is the leading cause of dependence and disability in the elderly population worldwide with Alzheimer's disease (AD) being by far the most common form. The absence of effective therapies causes major socioeconomic burden. Increasing evidence supports that AD is a metabolic disease with high diabetes co-morbidity and a wide range of metabolic perturbations occurring early in the disease process. While genetic risk clearly plays an important role in AD, it is also important to note that gut microbiome, the environment and life style might contribute to disease pathogenesis. Rapidly growing support for role of gut microbiome in human disease is emerging. Gut microbes complement human metabolism. For example, the gut-brain metabolic axis facilitates bidirectional chemical communication between the central and enteric nervous system through neuroactive metabolites, such as hormones, neurotransmitters among others. Changes in gut microbiome composition have been associated with a wide array of conditions, including neurological and neurodevelopmental disorders such as multiple sclerosis, autism, depression, schizophrenia and Parkinson's disease. In the AD Metabolomics Consortium (ADMC), which is funded by NIA as part of its national programs (AMP-AD and M2OVE-AD), we have created a comprehensive metabolomics database for AD to enable mapping of metabolic failures across the trajectory of disease. In two large Alzheimer's Disease Neuroimaging Initiative studies (ADNI-1 and ADNI-GO/2), the ADMC team has shown that bile acids (BAs), which are products of hepatic cholesterol metabolism and gut microbial activity, are dysregulated in AD. A decrease in primary BAs and an increase in bacterially produced secondary BAs correlated with cognitive decline, brain atrophy, and a reduction in brain glucose metabolism suggesting that the gut microbiome might play a role in AD pathogenesis. In addition, we have identified major changes in phospholipid and sphingolipid metabolism early in AD, correlating with CSF pathology, and changes in branched-chain amino acids, amines, and acylcarnitines, correlating with brain atrophy and cognitive decline as disease progressed. Many of these metabolites were recently shown to be regulated in part by gut microbiome activity. In this application, we bring the power of metabolomics, (meta)genomics and large clinical and community studies to gain further insights in the role of gut microbiome in AD mechanisms. We seek to define gut bacterial composition and activity that mediate aberrant bile acid, lipid and amine profiles as well as other blood metabolites and their relationship to AD pathogenesis. In addition, we will use cutting-edge computational systems biology techniques to identify human and microbial genes, reactions, and pathways and their interplay that are involved in AD pathogenesis. We will evaluate the role of the gut-brain metabolic axis in the development of AD, with the ultimate goal of defining human and microbial genes and proteins that may serve as potential therapeutic targets.